Intellectual disabilities (ID) and autism spectrum disorders (ASD) are highly prevalent disorders of developmental delay with substantial overlap. ID and ASD are highly heritable, but because of genetic heterogeneity only about 15% of ASD patients and 50% of ID patients have a specific genetic diagnosis. Identified genetic causes of ASD and ID suggest common genetic pathways in disease pathogenesis including synaptic dysfunction, cytoskeletal dynamics in spine development, the Ras-MAPK pathway, and histone modification. In collaboration with two fellows in the laboratory of my sponsor, Christopher A. Walsh, I have recently identified a large family from the Kingdom of Saudi Arabia and the United Arab Emirates with recessively inherited ID with autistic features. We have identified a truncating mutation in a novel, uncharacterized gene in all affected individuals from this family. An unanswered question in developmental neurobiology is how the various cellular pathways that contain identified ASD and ID genes are coordinated in normal cognitive development. Understanding the function of this gene, a predicted methyltransferase that may regulate multiple genes through protein modification, can provide insight into coordination between cellular pathways for cognitive development disrupted in ASD and ID. I propose the following experiments to investigate the function of this gene.
In Specific Aim 1, I will determine if the truncating mutation in this family is a loss of function allele, and will search for additional loss of function alleles in this gene in other ID and ASD patients.
In Specific Aim 2, I will characterize subcellular localization, interaction partners, and methyltransferase activity of the protein encoded by this gene.
In Specific Aim 3, I will collaborate with the lab of my co-sponsor, Michael Greenberg, to characterize neuron morphology and activity-dependent gene expression in the absence of this gene.

Public Health Relevance

This project will study the function of a novel, uncharacterized gene that we have found to be disrupted in a large family with intellectual disability and autistic features. I will study the function of this gene by identifying other genes with which it interacts and by measuring changes in mouse neurons when this gene is absent. These experiments will help us understand the underlying causes of intellectual disability and autism spectrum disorders.